A-norsteroids



United States Patent M Int. Cl. C07c 171/06 U.S. Cl. 260-310 4 Claims ABSTRACT OF THE DISCLOSURE A-norsteroids of the formulae CHnZ IQ m I CHnZ CHzZ 611 I CH3 V 0:

and their intermediates, wherein X is lower alkyl; R is hydrogen; R is hydroxy; and together R and R are oxo; and Z is hydrogen, hydroxy, halogen or acyloxy. They are prepared by reacting the corresponding A-nor-androstencs, A-nor-androstadienes or their 15-keto derivatives with diazomethane, heating the resulting pyrazoline derivatives, reacting the 6-methyl derivatives so formed with an acid halide, following this with a reaction with diazomethane and then with a fatty acid or with a hydrohalide and potassium acetate or the like. The resulting products possess anti-androgenic activity and may be employed in the treatment of hyperandrogenic acne.

This application is a division of my application, Ser. No. 308,693, filed Sept. 13, 1963, now U.S. Patent 3,393,- 230.

Patented Dec. 16, 1969 This invention relates to and has for its objects the provision of new physiologically active steroids, methods for their production, and novel intermediates useful in the preparation thereof.

The novel final products of the instant invention may be represented by the formulae CHzZ CHnZ 5:0 =0 R I I l (5H3 (5H; 0 0- l X X (IDHzZ CHaZ 0:0 (i=0 R\ I and 0 as,

wherein R is hydrogen; R is hydroxy; and together R and R is 0x0 (0:); X is lower alkyl (e.g., methyl) and Z is selected from the group consisting of hydrogen, hydroxy, acyloxy and halogen (e.g., chloro, fluoro, bromo or iodo).

The preferred acyloxy radicals are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g. acetic, propionic, butyric and tert.-pentanoic acid), the lower alkenoic acids, the monocyclic aryl carboxylic acids (e.g. benzoic and toluic acid), the monocyclic aryl lower alkanoic acids (eg phenacetic and ;3-phenylpropi0nic acid), the cycloalkane carboxylic acids and the cycloalkene carboxylic acids.

The products of this invention are physiologically active compounds which possess antiandrogenic activity and thus may be employed in the treatment of hyperandrogenic acne, for which purpose they may be administered, the dosage being adjusted for the relative potency of the particular steroid and the requirements of the patient.

The final products of this invention may be prepared by the processes of this invention, which entail a number of steps starting with the compounds represented by the following formulae wherein B is lower alkyl and R and R are as hereinbefore defined. The compounds which may be employed as starting materials in the practice of this invention may be prepared according to the procedures set forth in my copending applications Ser. No. 212,154, filed July 24, 1962 now US. Patent No. 3,170,919, and Ser. No. 308,677, now US. Patent No. 3,271,390, and include such compounds as methyl 14-methyl-A-nor-A -androstene-3,11- dione 175 carboxylate; methyl 14 methyl A nor- A androstadiene 3 one 17,8 carboxylate; methyl 14 methyl A nor A androstene 11p ol- 3 one 17B carboxylate; methyl 14 methyl A nor- A androstene 3,11,15 trione 17,8 carboxylate; methyl 14 methyl A nor A5301) androstadiene 3,15- dione 17,9 carboxylate; and methyl 14 methyl A- nor A androstene 115 ol 3,15 dione 17fl-carboxylate.

The process of the instant invention may be represented by the following equations, wherein X, R, R and Z are as hereinbefore defined:

COOB COOB I 2 I CH3 0: V 0- I CH3 E CH3 F VII B=CH3; R=H; R'=0H IX 3:011; VIII B=CH;; R&R=O=

(30A GOA R 11 I ,Q Ll

I CH3 G CH1 H X R=H; R -OH; A=halide (Cl, Br) XII A=halide XI R&R=O=; A=halide (Cl, Br) (Cl, Br)

(IJHN, CHN, C=O ;=0

I I I 0=Q om J CH; K

XIII R=H; R=OH XIV R&R'=0= (IJHIZ (IIHIZ 0:40 0

R I l I I CH; L CH; M

XV Z= ;R=H; R=OH XXIII Z=halide XVI Z=0H; R=H; R=OH XXIV Z=H XVII Z=CH3COO; R=H, R=OH XXV Z=OH XVIII Z=halide; R= ;R=OH XXVI Z=CHaCOO XIX Z=H; R8: :0:

XX Z=OH; R&R =0= XXI Z=Halide; R&R' =0= XXII Z=CH;COO; R&R :0:

In the first step of the process of this invention, the ll-substituted A-nor-A -androstenes (Compounds A) and the A-n0r-A -androstadienes (Compounds B) starting materials are reacted with a diazoalkane (e.g diazomethane) in the presence of a metal halide (e.g, aluminum chloride) to yield the respective pyrazoline derivatives thereof (Compounds C and D) which are new compounds of this invention.

Compounds C and D may then be heated at temperatures above their respective melting points to yield the respective 6-methyl-A -androstene (Compounds E) and the 6-methyl-A -androstadienes (Compounds P), which are also new compound of this invention.

Compounds E and F may then be treated with an acid halide, for example, oxalyl chloride, to obtain the corresponding 11-substituted 6-methyl-A-nor-A -androstene-17- carboxylic acid halides (Compounds G) and the 6-methy1- A-nor-A -androstadiene-17-carboxylic acid chlorides (Compounds H) respectively, which are also new compounds of this invention.

These acid chloride compounds (Compounds G and H) are then converted to their respective diazoketone-6- methyl-A-nor-M-pregenes (Compounds J) and diazoketone-6-methyl-A-nor-A pregnadienes (Compounds K), which are also new compounds of this invention, by treatment with an ethereal solution of diazomethane.

In order to obtain the final products of this invention which are oxygenated in the 21-position (i.e., Z is acyloxy or hydroxy). Compounds J and K are treated at elevated temperature with a fatty acid, for example, acetic, propionic or butyric acid, to yield the 21-esters of 11-substituted 6 methyl A nor A pregnenes (Compounds L) and 6-methyl-A-nor-A -pregnadienes (Compounds M), which are also new compounds of this invention. Alternatively, Compounds L and M (wherein Z is acyloxy) may be obtained by first treating Compounds J and K with a hydrohalide, for example, hydrochloric acid, to yield the 21-halogenated-A-nor-pregnenes (Compounds L and M, wherein Z is halide), which are also new compounds of this invention, and then substituting the 2l-halide-A-nor-pregnenes as by treatment with potasium iodide and potassium acetate to yield the respective 21-acyloxy-A-nor-pregnenes (Compounds L and M). To obtain the 2l-hydroxy-A-nor-pregnene compounds of this invention (Compounds L and M, wherein Z is hydroxy), the 21-acyloxy compounds are treated with a base, such as potassium carbonate. The 2l-hydroxy-6-methyl-A-norpregnenes (Compounds L and M, wherein Z is hydroxy) are also new compounds of this invention.

To obtain the final compounds of this invention, which are not oxygenated in the 21-position (i.e. wherein Z is hydrogen or halogen), Compounds I and K are first treated with hydriodic acid to yield the 2l-unsubstituted- A-norpregnenes (Compounds L and M, wherein Z is hydrogen), which are also new compounds of this invention.

The 21-halogenated compounds are obtained as set forth hereinabove, i.e., by treatment of Compounds J and K with a hydrohalide, e.g., hydrochloric acid. It should be noted that when the IS-keto starting materials are employed in the practice of this invention, the final products thereof and the intermediates produced thereby will all be the -keto derivatives of the compounds set forth hereinabove. These compounds are also new compounds of this invention.

The invention may be further illustrated by the following examples:

EXAMPLE 1 Methyl 14-methyl-5,6-pyrazolino-A-norandrostane- 3,l l-dione-l7fi-carboxylate (II) To a suspension of 50 mg. of finely powdered methyl l4 methyl A-nor-A -androstene-3,ll-dione-l7 3-carboxylate (I) in 30 m1. of ethereal diazomethane solution is added at room temperature, in portions, a total of mg. of aluminum chloride which had been aged by leaving it exposed to the atmosphere for 5-10 minutes. The total reaction time is one hour and thirty minutes. The excess diazomethane is then destroyed by the addition of two drops of glacial acetic. The mixture is Washed with water and the ether extract evaporated to dryness in vacuo. The resulting residual mixture is purified by preparative thin layer chromatography on activity V neutral alumina using chloroform as the moving phase. Two zones are obtained, designated as A and B. The elution of zone A furnishes after concentration 21 mg. of material, M.P. 200201, which is identified as starting material. Elution of zone B furnishes after crystallization from methanol 9 mg. of methyl 14-methyl-5,6-pyrazolino-A-norandrostane- 3,11-dione-17fl-carboxylate which melts with decomposition at 176-178; [a] +360 (c., 0.28 in chloroform);

Analysis.-Calcd. for C H O N (386.48): C, 68.37;

H, 7.82. Found: C, 68.43; H, 7.81.

EXAMPLE 2 Methyl 14-methyl-5,6-pyrazolino-A-nor-A androstene-3-one-17,8-carboxylate Following the procedure set forth in Example 1 but substituting an equivalent amount of methyl 14-methyl-A- nor-A -androstadiene-3-one-17,B-carboxylate for methyl 14-methyl-A-nor-A -androstene-3,l 1-dione-17/3-carboxylate, there is obtained methyl l4-methyl-5,6-pyrazolino- A-nor-A -androstene-3-one-l7fl-carboxylate.

EXAMPLE 3 Methyl 14-methyl-5,-6-pyrazolino-A-n0randrostane- 11B-ol-3-one-17fl-carboxylate Following the procedure set forth in Example 1, but substituting an equivalent amount of methyl 14-methyl-A- nor-A -androstene-11,8-ol-3-one-l7B-carboxylate for methyl 14-methyl-A-nor-A -androstene-3, 1 1-dione-17fi-carboxylate, there is obtained methyl 14-methyl-5,6-pyrazolino- A-norandrostane-l 1,8-01-3-one-17B-carboxylate.

EXAMPLE 4 Methyl 6, 14-dimethyl-A-nor-A -androstene-3,1 1- dione-17/3-carboxylate (III) A3??? 255 m,a(e=8,600); REE; 5.75, 5.86, 6.10n EXAMPLE 5 Methyl 6,14-dimethyl-A-nor-A -androstadiene- 3-one- 17 ,B-carboxylate Following the procedure set forth in Example 4, but substituting an equivalent amount of methyl l4-methyl- 5,6 pyrazolino A-nor-A -androstene-1713-carboxylate for methyl 14-methyl-5,6-pyrazolino-A-norandrostane-3, l1-dione-l7B-carboxylate, there is obtained methyl 6,14 dimethyl A-nor-A -androstadiene-3 -one-17(3-carboxylate.

EXAMPLE 6 Methyl 6,14-dimethyl-A-nor-A -androstene-1 1(3- ol-3-one-17/3-carboxylate Following the procedure set forth in Example 4, but substituting an equivalent amount of methyl 14-methyl- 5,6 pyrazolino A-norA -androstene-l1B-ol-3-one-17B- carboxylate for methyl 14-methyl-A-nor-A -androstene-3, 20-dione-17,3-carboxylate, there is obtained methyl 6,14- dime'thyl A-nor-A -androstene-1lfl-ol-3-one-l7/3-carboxylate.

EXAMPLE 7 6,14-dimethyl-A-nor-A -androstene-3,1 l -dione- 17,8- carboxylic acid To a mxiture of KOH in methanol and water, which has been refluxed for 10 minutes and cooled under a blanket of helium is added methyl 6,l4-dimethyl-A-nor- A -androstene-3,11-dione-17fi-carboxylate and the resulting solution is refluxed under a blanket of helium. The mixture is then cooled and after the addition of glacial acetic acid is diluted with Water. After the removal of the bulk of the methanol in vacuo the 6,14-dimethyl-A- nor-A -androstene-3,ll-dione-17B-carboxylic acid crystallizes and is filtered and washed with water.

EXAMPLE 8 6,14-dime'thyl-A-nor-A -androstadiene-3-one- Nit-carboxylic acid Following the procedure set forth in Example 7 but substituting an equivalent amount of methyl 6,14-methyldimethyl A-nor-A -androstadiene-3-one-l7B-carb0xylate for methyl 6,14-dimethyl-A-nor-A -androstene-3,11- dione-17fi-carboxylate, there is obtained 6,14-dimethyl-A- norA -androstadiene-3-one-Uri-carboxylic acid.

EXAMPLE 9 6, l4 dimethyl-A-nor-A -androstene-1 113-o1-3-one- 19fl-carboxylic acid Following the procedure in Example 7 but substituting an equivalent amount of methyl 6,14-dimethyl-Anor-A androstene-l1fl-ol-3-one-17B-carboxylate for methyl 6,14- dimethyl A-nor-A -androstene-3,11-dione-175-carboxylate, there is obtained 6,l4-dimethyl-A-nor-A -androstene- 11B-o1-3-one-HIE-carboxylic acid.

EXAMPLE 10 6,14-dimethyl-A-nor-A -androstene-3 ,1 l-dione- 17 B- carboxylic acid chloride To a suspension of vacuum dried, 6,14-dimethyl-A-nor- A -androstene-3,11-dione-17B-carboxylic acid in anhydrous benzene is added with stirring redistilled oxalyl chloride. After 30 minutes all the acid has dissolved and the solution is allowed to remain at room temperature for an additional 40 minutes. Upon the removal of the solvent in vacuo there remains a crystalline solid to which is added anyhdrous benzene and the later removed again in vacuo, thus yielding 6,14-dimethyl-A-nor-A -androstene-3,1l-dione-17,8-carboxylic acid chloride.

EXAMPLE l1 6, 14-dimethyl-A-nor-A -androstadiene-3-one- MIR-carboxylic acid chloride Following the procedure set forth in Example 10 but substituting an equivalent amount of 6,14-dimethyl-A- nor-A -androstadiene-3-one-17;3-carboxylic acid for 6,14 dimethyl A-nor-A -andrstene-3,1I-dione-17e-carboxylic acid there is obtained 6,14-dimethyl-A-norA androstadiene-3-one-Uri-carboxylic acid chloride.

EXAMPLE 12 6,14-dimethyl-A-nor-A -androstene-1 1B-ol-3-one- 17 fi-carboxylic acid chloride Following the procedure set forth in Example but substituting an equivalent amount of 6,14-dimethyl-A-nor- A -androstene-11,8-ol-3-one 17fl-carboxylic acid for 6,14- dimethyl A-nor-A -androstene-3,11-dione-17fl-carboxy1ic acid there is otbained 6,14-dimethyl-A-n0rA -androstene- EXAMPLE 13 6,14-dimethyl-21-diazo-A-nor-A -pregnene-3,1 1-,20-trione A solution of 6,14-dimethyl-A-nor-A -androstene-3,Ildione-17/8-carboxylic acid chloride in anhydrous benzene is added at 0 C. to a concentrated distilled solution of diazomethane in ether. The mixture is allowed to warm up to room temperature and after a total reaction time of 1% hours it is filtered from flocculent polyethylene and evaporated to dryness in vacuo. The resulting crystalline residue is recrystallized from methanol and furnishes 6,14- dimethyl-21-diazo-A-IlOr-M-pregnene-Ii,1 1,20-trione.

8 EXAMPLE 14 6,14-dimethyl-21-diazo-A-nor-A -pregnadiene- 3,20-dione To a solution of 6,14-dimethyl-21-diazo-A-nor-A -pregnene-3,11,20-trione is added at 0 C. a saturated solution of hydrogen chloride in chloroform. The mixture is allowed to remain at 0 C. for 20 minutes after which time it is extracted with dilute sodium bicarbonate. The chloroform extract is dried over sodium sulfate, evaporated to dryness and the residual crystalline recrystallized from methanol yielding 6,14-dimethyl-21-chloro-A-nor-A -pregnene-3, l 1,20-trione.

Similarly, following the procedure of Example 16 but substituting hydrogen bromide for the hydrogen chloride there is obtained 6,1-4-dimethyl-21-bromoA-nor-A -pregnene-3,11,20-trione.

Similarly, when a limited amount of hydrogen iodide is substituted for the hydrogen chloride, 6,14-dimethyl-2liodo-A-nor-A -pregnene-3,11,20-trione is obtained.

EXAMPLE 17 6,14-dimethyl-21-chloro-A-nor-A -pregnadiene- 3,20-dione Following the procedure set forth in Example 16 but substituting an equivalent amount of 6,14-dimethyl-21- diazo-A-nor-A -pregnadiene-3,20-dione for 6,14-dimethyl-21-diazo-A-nor-A -pregnene-3,11,20-trione there is obtained 6,14-dimethyl-2l-chloro-A-nor-A -pregnadiene-3,20-dione.

EXAMPLE 18 6, 14-dimethyl-21-chloro-A-nor-A -pregnene-1 113- ol3,20-dione Following the procedure set forth in Example 16 but substituting an equivalent amount of -6,14 dimethyl-21- diazo-A-nor-M-pregnene-11,8-ol-3,20-dione for 6,14-dimethyl-21-diazo-A-nor-A -pregnene-3,11,20-trione there is obtained 6,14-dimethyl-21-chloro-A-nor-A -pregnene-115- ol-3,20-di0ne.

EXAMPLE 19 6,14-dimethyl-A-nor-A -pregnene-3,11,20-trione To a solution of 6,14-dimethyl-21-diazo-A-nor-A -pregnene-3,11,20-trione in chloroform is added under a blanket of carbon dioxide freshly distilled aqueous hydriodic acid. The mixture is thoroughly mixed by shaking for 3 minutes at room temperature, poured into water and chloroform and the chloroform solution extracted with dilute sodium bicarbonate with the addition of a small amount of sodium bisulfite. The chloroform extract is then washed with water, dried over sodium sulfate and evaporated to dryness in vacuo and the residue crystallized from methanol to yield 6,14-dimethyl-A-nor-M-pregnene-3,11,20- trione.

9 EXAMPLE 2o 6,14-dimethyl-A-nor-A -pregnadiene-3,20-dione Following the procedure set forth in Example 19 but substituting 6,14-dimethyl-21-diazo-A-nor-A -pregnadiene-3,20-dione for 6,14-dimethyl-2l-diazo-A-nor-A pregnene 3,11,20 trione yields 6,14 dimethyl-A-nor- A -pregnadiene-S,ZO-dione.

EXAMPLE 21 6, 14-dimethyl-A-nor-A -pregnene-1 1 8-ol-3,20-dione Following the procedure set forth in Example 19 but substituting an equivalent amount of 6,14-dimethyl-2ldiazo-A-nor-M-pregnene-llB-ol-3,20-dione for 6,14-dimethyl-21-diazo-A-nor-A -pregnene-3,11,20-trione yields 6, l4-dimethyl-A-nor-A -pregnene-1 1,8-01-3,20-dione.

EXAMPLE 22 6, l4-dimethyl-A-nor-A -pregnene-21-01-3 ,1 1,20-trione- 2 l-acetate A solution of 6,l4-dimethyl-2l-diazo-A-nor-A -pregnene-3,l1,20-trione in glacial acetic acid is heated on the steam bath for /2 hour. Water and chloroform are added and the resulting chloroform extract washed with sodium bicarbonate and water, dried over sodium sulfate and the solvent evaporated to dryness in vacuo. The residual crystals obtained after recrystallization from methanol yield 6,14 dimethyl A-nor-A -pregnene-21-ol3,11,20-trione- 2l-acetate.

Similarly, substituting propionic acid, butyric acid or other fatty acids for the acetic acid for Example 22 there are obtained the corresponding propionic, butyric and other esters of 6,l4-dimethyl-A-nor-A -pregnene-21-ol-3, 11,20-trione.

EXAMPLE 23 6, l4-dirnethyl-A nor-A -pregnadiene-21-ol- 3,20-dione-21-acetate Following the procedure set forth in Example 22 but substituting 6,14 dimethyl 2l-diazo-A-nor-A pregnadiene-3,20-dione for 6,14-dimethyl-21+diazo-A-nor-A pregnene 3,11,20 trione yields 6,14 dimethyl-A-nor- A -pregnadiene-21-ol-3,20-dione-2l-acetate.

EXAMPLE 24 6,l4-dimethyl-A-nor-M-pregnene-1lB,21-diol-3,20 dione-21-acetate Following the procedure set forth in Example 22 but substituting 6,14 dimethyl 21-diazo-A-nor-A -pregnenellfl ol 3,20-dione for 6,l4-dimethyl-2l-diazo-A-nor-A pregnene 3,11,20 trione yields 6,14-dimethyl-A-nor-A pregnene-l1,8,2l-diol-3,20-dione-2l-acetate.

EXAMPLE 25 6,14-dimethyl-A-nor-A -pregnene-2l-ol-3,l 1,20-trione To a solution of 6,14-dimethyl-A-nor-A -pregene-2l-ol- 3,11,20-trione-2l-acetate in methanol is added with stirring under nitrogen oxygen-free potassium carbonate. After 2 hours at room temperature glacial acetic acid is added and after the addition of water the methanol is removed in vacuo. The mixture is then extracted with chloroform, the chlorofrom extract washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The resultant crystallized 6,14-dimethyl-A-nor-A pregnene-2l-ol-3,11,20-trione is then recrystallized from acetone hexane.

10 EXAMPLE 26 6,14-dimethyl-A-nor-A -pregnene-Zl-ol-3,20-dione Following the procedure set forth in Example 25 but substituting 6,14 dimethyl A-nor-A -pregnadiene- 21 ol 3,20-dione-2l-acetate for 6,l4-dimethyl-A-nor-A pregnene-21-ol-3,l1,20-trione-2l-acetate there is obtained 6,14-dimethyl-A-nor-A -pregnenc-21-ol-3,20-dione.

EXAMPLE 27 6, l4-dimethyl-A-nor-A -pregnene-1 1,8,21 -diol-3,20-dione Following the procedure set forth in Example 25 but substituting 6, l4-dimethyl-A-nor-A -pregnene-l 15,2 l-diol- 3,20 dione 21-acetate for 6,14-dimethyl-A-nor-A -pregnene-2l-ol-3,11,20-trione-2l-acetate there is obtained 6,14- dirnethyl-A-nor-A -pregnene-1 16,2 l-diol-3,20-dione.

What is claimed is:

1. A compound selected from the group consisting of steroids of the formulae wherein W is methylene; R is hydrogen, R is hydroxy, R and R together are oxo and B is hydrogen or lower alkyl.

2. Methyl 14 methyl-5,6-pyrazolino-A-norandrostane- 3,1l-dione-l7B-carboxylate.

3. Methyl 14 methyl 5,6-pyrazolino-A-nor-A -androstene-3-one-l7fi-carboxylate.

4. Methyl 14 methyl 5,6-pyrazolino A-norandrostane- 1 1 8-01-3-one- 17,8-carboxylate.

References Cited UNITED STATES PATENTS 3,030,358 4/1962 Manson 260--239.5 3,067,193 12/1962 Tishler et al. 260239.5 3,129,218 4/1964 Fried et a1. 260-2395 3,345,387 10/1967 Taub et a1. 260-239.5 3,350,394 10/1967 Agnello et al 260239.5

OTHER REFERENCES Elderfield Heterocyclic Compounds, vol. 5, pp. 72-84, New York, Wiley, 1957.

NORMA S. MILESTONE, Primary Examiner NATALIE TROUSOF, Assistant Examiner I US. Cl. X.R. 260-999 

